Pharmaceutical researchers have discovered that the neurons of the brain which contain monoamines are of extreme importance in a great many physiological processes which affect many psychological and personality-affecting processes as well. In particular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be a key to a very large number of processes which affect both physiological and psychological functions. Drugs which influence the function of serotonin in the brain are accordingly of great importance and are now used for a large number of different therapies.
The early generations of serotonin-affecting drugs tended to have a variety of different physiological functions, considered from both the mechanistic and therapeutic points of view. For example, many of the tricyclic antidepressant drugs are now known to be active as inhibitors of serotonin reuptake, and also to have anticholinergic, antihistaminic or anti-xcex1-adrenergic activity. More recently, it has become possible to study the function of drugs at individual receptors in vitro or ex vivo, and it has also been realized that therapeutic agents free of extraneous mechanisms of action are advantageous to the patient.
The present invention provides compounds which have highly selective activity as antagonists and partial agonists of the serotonin 1A receptor and a second activity as inhibitors of reuptake of serotonin. The best-known pharmaceutical with the latter efficacy is fluoxetine, and the importance of its use in the treatment of depression and other conditions is well documented and publicized. Artigas, TIPS, 14, 262 (1993), have suggested that the efficacy of a reuptake inhibitor may be decreased by the activation of serotonin 1A receptors with the resultant reduction in the firing rate of serotonin neurons. Accordingly, present research in the central nervous system is focusing on the effect of combining reuptake inhibitors with compounds which affect the 5-HT1A receptor.
Compounds exhibiting both serotonin reuptake inhibition activity and 5-HT1A antagonist activity have been described, for example, in U.S. Pat. No. 5,576,321, issued Nov. 19, 1996. Compounds of the present invention are potent serotonin reuptake inhibitors and antagonists of the 5-HT1A receptor.
The present invention provides compounds of formula I: 
wherein
A is hydrogen, OH or (C1-C6) alkoxy:
B is selected from the group consisting of: 
represents a single or a double bond;
X is hydrogen, OH or C1-C6 alkoxy when represents a single bond in the piperidine ring, and X is nothing when represents a double bond in the piperidine ring;
Y is S or CH2;
R1 is hydrogen, F, C1-C20 alkyl, xe2x80x94C(xe2x95x90O)NR8R9, or CN;
R2 is hydrogen, F, Cl, Br, I, OH, C1-C6 alkyl or C1-C6 alkoxy;
R3 and R4 are each independently hydrogen or C1-C4 alkyl;
R5 and R6 are each independently hydrogen, F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, phenyl, xe2x80x94C(xe2x95x90O)NR8R9, NO2, NH2, CN, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F,
Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, NO2, NH2, CN, and phenyl;
R7 is hydrogen, F, Cl, Br, I, OH, C1-C6 alkyl or (C1-C6 alkyl)NR8R9;
R8 and R9 are each independently hydrogen or C1-C10 alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2;
p is 0, 1, 2, 3 or 4; and
q is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of inhibiting the reuptake of serotonin and antagonizing the 5-HT1A receptor which comprises administering to a patient an effective amount of a compound of formula I.
More particularly, the present invention provides a method for alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine; a method of treating anxiety; and a method of treating a condition chosen from the group consisting of depression, hypertension, cognitive disorders, Alzheimer""s disease, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder, and migraine; which methods comprise administering to a patient an effective amount of a compound of formula I.
In addition, the present invention provides a method of potentiating the action of a serotonin reuptake inhibitor comprising administering to a patient an effective amount of a compound of formula I in combination with an effective amount of a serotonin reuptake inhibitor.
In addition, the invention provides pharmaceutical compositions of compounds of formula I, including the hydrates thereof, comprising, as an active ingredient, a compound of formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula I.
According to another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof as defined hereinabove for the manufacture of a medicament for inhibiting the reuptake of serotonin and antagonizing the 5-HT1A receptor.
According to yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove for inhibiting the reuptake of serotonin and antagonizing the 5-HT1A receptor.
It is understood that the compounds of formula Ia: 
are included within the scope of the definition of formula I wherein the substituents are defined as hereinabove.
It is further understood that the compounds of the formula Iaa: 
are included within the scope of the definition of formula I wherein the substituents are defined as hereinabove.
As used herein, the terms xe2x80x9cMexe2x80x9d, xe2x80x9cEtxe2x80x9d, xe2x80x9cPrxe2x80x9d, xe2x80x9ciPrxe2x80x9d, xe2x80x9cBuxe2x80x9d and xe2x80x9ct-Buxe2x80x9d refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, respectively.
As used herein, the terms xe2x80x9cHaloxe2x80x9d, xe2x80x9cHalidexe2x80x9d or xe2x80x9cHalxe2x80x9d refer to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein the term xe2x80x9cC1-C10 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
As used herein the term xe2x80x9cC1-C20 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl and the like.
As used herein the term xe2x80x9chalo(C1-C6)alkylxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(C1-C6)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. The term xe2x80x9chalo(C1-C6)alkylxe2x80x9d includes within its definition the term xe2x80x9chalo(C1-C4)alkylxe2x80x9d.
As used herein the term xe2x80x9cC1-C6 alkoxyxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term xe2x80x9cC1-C6 alkoxyxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkoxyxe2x80x9d.
The designation xe2x80x9cxe2x80x9d refers to a bond that protrudes forward out of the plane of the page.
The designation xe2x80x9cxe2x80x9d refers to a bond that protrudes backward out of the plane of the page.
This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1,4-dioate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, phthalate, p-toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex1-hydroxybutyrate, glycolate, tartrate, benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate, tartarate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                -                  E          2                                      E          1                +                  E          2                      xc3x97    100  
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formulas I or Ia can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981.
Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
The specific stereoisomers and enantiomers of compounds of formula (I) can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, xe2x80x9cStereochemistry of Organic Compoundsxe2x80x9d, John Wiley and Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. For example, the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
As used herein, the term xe2x80x9cSRIxe2x80x9d refers to serotonin reuptake inhibitor.
As used herein the term xe2x80x9cserotoninxe2x80x9d is equivalent to and interchangeable with the terms xe2x80x9c5-HTxe2x80x9d or xe2x80x9c5-hydroxytryptaminexe2x80x9d.
As used herein, xe2x80x9cPgxe2x80x9d refers to a protecting group on the amine which is commonly employed to block or protect the amine while reacting other functional groups on the compound. Examples of protecting groups (Pg) used to protect the amino group and their preparation are disclosed by T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John Wiley and Sons, 1981, pages 218-287. Choice of the protecting group used will depend upon the substituent to be protected and the conditions that will be employed in subsequent reaction steps wherein protection is required, and is well within the knowledge of one of ordinary skill in the art. Preferred protecting groups are t-butoxycarbonyl also known as the BOC protecting group, and benzyloxycarbonyl.
The compounds of formula I can be prepared by techniques and procedures readily available to one of ordinary skill in the art. For example, various starting materials and general procedures which may be employed by one of ordinary skill in the art in the preparation of compounds of formula I are described in U.S. Pat. No. 3,929,793, issued Dec. 30, 1975, U.S. Pat. No. 4,304,915, issued Dec. 8, 1981, U.S. Pat. No. 4,288,442, issued Sep. 8, 1981, U.S. Pat. No. 4,361,562, issued Nov. 30, 1982, U.S. Pat. No. 4,460,586, issued Jul. 17, 1984, U.S. Pat. No. 4,704,390, issued Nov. 3, 1987, U.S. Pat. No. 4,935,414, issued Jun. 19, 1990, U.S. Pat. No. 5,013,761, issued May 7, 1991, and U.S. Pat. No. 5,614,523, issued Mar. 25, 1997. More specifically, compounds of formula I can be prepared by following the procedures as set forth in Schemes I through IV. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. More specifically, Schemes I through II provide general syntheses of various intermediate piperidines. 
In Scheme I, step A, compound (1) is added to piperidone (2) under conditions well known in the art, to provide the alcohol (3). For example, an appropriately substituted naphthalene, such as 2-bromonaphthalene, 1-bromo-5-methoxy-naphthalene, 2-bromo-7-methoxy-naphthalene, 6-iodo-1-methoxy-naphthalene, and the like, is dissolved in a suitable organic solvent, such as tetrahydrofuran and cooled to about xe2x88x9278xc2x0 C. To this stirring solution is added an excess of a suitable base, such as t-butyllithium. The mixture is stirred for about 1 to 3 hours, and 1.0 to about 1.1 equivalents of the piperidone (2) are added. The reaction is allowed to warm to room temperature and the alcohol (3) is isolated and purified by techniques well known in the art. For example, the mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude alcohol can then be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the purified alcohol (3). Alternatively, the crude isolated alcohol (3) can be carried directly onto the next step.
The piperidones (2) are readily available to one of ordinary skill in the art utilizing known starting materials. For example, I.V. Micovic, et al., J. Chem. Soc., Perkin Trans., 1(16), 2041-2050 (1996) teach the preparation of variously substituted piperidine-2,4-diones. Such piperidine-2,4-diones can be selectively protected, alkylated, and reduced under conditions well known in the art to provide the desired piperidone (2). For example, compounds of the formula (2axe2x80x2) 
can be prepared in a manner analogous to the procedure described by Micovic et al. above, which can then be reduced to provide the 2,2-disubstituted-N-protected-4-piperidone (2axe2x80x3). 
In Scheme I, step B, the alcohol (3) is dehydrated under standard conditions to provide the 1,2,5,6-tetrahydropiperidine (4) wherein Pgxe2x80x2 is maintained as a protecting group and does not represent hydrogen. For example, the alcohol (3) is dissolved in a suitable organic solvent, such as toluene, and treated with an excess of a suitable acid, such a p-toluenesulfonic acid monohydrate. The reaction mixture is heated at reflux for about 6 to 12 hours and then cooled. The 1,2,5,6-tetrahydropiperidine is then isolated and purified under conditions well known in the art. For example, the cooled reaction mixture is basified with 2 N sodium hydroxide and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude residue is then purified by flash chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride to provide the purified 1,2,5,6-tetrahydropiperidine (4).
Alternatively, in Scheme I, step B the alcohol (3) can be dehydrated and deprotected concomitantly under standard conditions to provide the compound (4) wherein Pgxe2x80x2 is hydrogen. For example, alcohol (3) wherein the protecting group is N-t-butoxycarbonyl, is dissolved in a suitable organic solvent, such as dry dichloromethane and the solution is cooled to about 0xc2x0 C. To this solution is added excess trifluoroacetic acid and the reaction mixture is stirred at about 0xc2x0 C. for about 15 h. The reaction is then quenched at room temperature with saturated aqueous NaHCO3 solution. The product is then isolated by techniques well known in the art, such as extraction, and then purified by flash chromatography. For example, the mixture is extracted with a suitable organic solvent, such as dichloromethane, the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude compound (4). This material can be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
In Scheme I, step C, the 1,2,5,6-tetrahydropiperidine (4) is hydrogenated under conditions well known in the art to provide a mixture of piperidines (5a) and (5b). For example, the 1,2,5,6-tetrahydropiperidine (4) is dissolved in a suitable organic solvent, such as ethanol and treated with a suitable catalyst, such as 5% palladium on carbon. The mixture is then placed under an atmosphere of hydrogen and stirred for about 12 hours at room temperature. The reaction mixture is then filtered to remove the catalyst and the filtrate is concentrated under vacuum to provide a mixture of isomers (5a) and (5b). It is readily appreciated by one of ordinary skill in the art that various isomers may exist at this step wherein the R groups can be either cis or trans to the naphthyl group. It is further recognized that these isomers may be separated from one another by techniques well known in the art, such as flash chromatography, radial chromatography or high performance liquid chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride. Alternatively, the mixture of isomers may be carried on to the next step or the separated isomers may individually be carried on to the next step.
In Scheme I, step D, wherein Pgxe2x80x2 is a protecting group and not hydrogen, the piperidines (5a) and (5b) are deprotected under conditions well known to one of ordinary skill in the art to provide piperidines (6a) and (6b). For example, when Pg is a methyl group, the piperidines (5a) and (5b) are dissolved in a suitable organic solvent, such as dichloroethane and cooled to about 0xc2x0 C. The cooled solution is then treated with an excess of 1-chloroethylchloroformate. The reaction is then allowed to warm to room temperature and then heated at reflux for about 12 hours. After cooling, the solvent is then removed under vacuum and the residue is dissolved in a suitable organic solvent, such as methanol. The solution is then heated at reflux for about 2 to 4 hours, cooled to room temperature, and then concentrated under vacuum. The residue is treated with water and a suitable organic solvent, such as ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic extracts, including the first organic phase, are combined, rinsed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude piperidines (6a) and (6b). The mixture can then be separated into purified individual stereoisomers if they were not already separated in step C using similar techniques, such as flash chromatography, radial chromatography or high performance chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
It is readily appreciated by one of ordinary skill in the art that the sequence of steps of dehydration, deprotection, and reduction can be varied depending upon the protecting groups utilized and the ultimate products desired. The conditions required for varying the sequence are well within the knowledge of one of ordinary skill in the art. 
In Scheme IA, the steps A through D are carried out in a manner analogous to the procedures set forth in Scheme I, steps A through D respectively. 
In Scheme IB, alcohol (3a) is alkylated under standard conditions to provide the ether (3b). For example, alcohol (3a), wherein the protecting group is N-t-butoxycarbonyl, is dissolved in a suitable organic solvent, such as dry MeOH and the solution is cooled to about 0xc2x0 C. To this solution is added excess trifluoroacetic acid. The reaction mixture is then stirred at room temperature for about one to 6 days. The reaction is then quenched at room temperature with saturated aqueous NaHCO3 solution, extracted with a suitable organic solvent such as dichloromethane, the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude ether (3b). The crude ether (3b) can then be purified by flash chromatography on silica gel with a suitable eluent, such as 7% (10% conc. NH4OH in MeOH)/CH2Cl2. 
In Scheme IC, alcohol (3a) can be deprotected without dehydration under standard conditions well known in the art, through appropriate choice of protecting groups, to provide the deprotected alcohol (3bxe2x80x2). For example, the alcohol (3a), wherein the protecting group is a xe2x80x94CH2CHxe2x95x90CH2 group, is dissolved in a suitable solvent, such as aqueous ethanol (10% H2O). The solution is then treated with chlorotris(triphenylphosphine) rhodium(I) (Wilkinson""s catalyst) and approximately 50% of the solvent is then distilled off over a period of about 1 hour. An additional 65 mL of solvent and 45 mg of Wilkinson""s catalyst is added and the reaction mixture is refluxed for about 1 hour and then the solvent is again distilled off to about 50% volume. The reaction mixture is then evaporated and the residue is purified using silica gel chromatography with a suitable eluent, such as dichloromethane/20% methanol, 2% anhydrous ammonia in dichloromethane gradient, to provide the purified deprotected alcohol (3bxe2x80x2). 
In Scheme II, step A, a naphthylboronic acid (7), such as 2-naphthylboronic acid is combined with the 1,2,5,6-tetrahydropiperidine (8) to provide the coupled compound (9). For example, about 1 to 1.5 equivalents of a naphthylboronic acid (7) is combined with about 1 equivalent of 1,2,5,6-tetrahydropiperidine (8), about 2 equivalents of lithium chloride, a catalytic amount of tetrakis(triphenylphosphine)palladium(0) in a mixture of 2 M aqueous sodium carbonate and tetrahydrofuran. The mixture is heated at reflux for about 12 hours and then cooled to room temperature. The reaction is then treated with 2 N sodium hydroxide and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, rinsed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude residue is then purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane to provide the compound (9).
In Scheme II, step B, compound 9 is hydrogenated under standard conditions to provide the piperidines (10a) and (10b). For example, compound (9) is dissolved in a suitable organic solvent, such as methanol, treated with a suitable catalyst, such as 5% palladium on carbon and stirred under an atmosphere of hydrogen for about 12 hours at room temperature. The reaction mixture is then filtered to remove the catalyst and the filtrate is concentrated under vacuum to provide piperidines (10a) and (10b). As noted in Scheme I, step C, it is readily appreciated by one of ordinary skill in the art that various isomers may exist at this particular step wherein the R groups can be either cis or trans to the naphthyl group. It is further recognized that these isomers may be separated from one another by techniques well known in the art, such as flash chromatography, radial chromatography or high performance liquid chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride. Alternatively, the mixture of isomers may be carried on to the next step or the separated isomers may individually be carried onto the next step.
In Scheme II, step C, the piperidines (10a) and (10b) are deprotected under conditions well known in the art to provide the piperidines (6a) and (6b). For example, piperidines (10a) and (10b) are dissolved in a suitable solvent mixture, such as 50% water/isopropanol and treated with an excess of a suitable base, such as potassium hydroxide. The reaction mixture is then heated at reflux for about 1 to 3 days and then cooled to room temperature. 2 N sodium hydroxide is added and the reaction is extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, rinsed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude residue is then purified by flash chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride to provide the purified piperidines (6a) and (6b). The mixture can then be separated into individual stereoisomers if they were not already separated in step C using similar techniques, such as flash chromatography, radial chromatography or high performance chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
It is readily appreciated by one of ordinary skill in the art that compounds (4), (4xe2x80x2) and (9) can be deprotected prior to reduction and the unsaturated deprotected piperidines can be used directly in Schemes III and IV. 
In Scheme IIA, step A, a 2-halo-benzothiazole (11), such as 2-chloro-4-fluorobenzothiazole, is combined with the 1,2,5,6-tetrahydropiperidine (8), to provide the coupled compound (9xe2x80x2). For example, about 1 equivalent of a 2-halo-benzothiazole (11) is combined with about 1.2 equivalents of 1,2,5,6-tetrahydropiperidine (8), about 1 equivalent of bis(trimethyltin), about 3 equivalents of lithium chloride, and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) in a suitable organic solvent, such as 1,4-dioxane. The mixture is heated at reflux for about 20 hours and then cooled to about 20xc2x0 C. The reaction is then treated with saturated potassium fluoride and ethyl acetate, and stirred for about 2 hours. The organic phase is separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude residue is then purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane to provide the compound (9xe2x80x2).
In Scheme IIA, Step B, compound (9xe2x80x2) is deprotected under standard conditions to provide compound (12). For example, compound (9xe2x80x2) is dissolved in a suitable organic solvent, such as dichloromethane, cooled to about 0xc2x0 C. and treated with an excess of trifluoroacetic acid. The mixture is then stirred for about 30 minutes, then warmed to about 20xc2x0 C. and stirred for an additional 20 minutes. The mixture is then diluted with 2 N sodium hydroxide and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound (12). Compound (12) can then be purified by flash chromatography on silica gel with a suitable eluent, such as (dichloromethane/10% methanol 1% ammonium hydroxide in dichloromethane gradient elution) to provide the purified compound (12).
In Scheme IIA, step C, compound (12) is hydrogenated under standard conditions to provide the cis and trans isomers (6axe2x80x3) and (6bxe2x80x3). For example, compound (12) is dissolved in a suitable organic solvent, such as ethanol and treated with a catalytic amount of platinum oxide. The mixture is then hydrogenated under 1 atmosphere for about 20 hours, filtered and the filtrate concentrated under vacuum to provide the cis and trans isomers (6axe2x80x3) and (6bxe2x80x3). The compounds can then be separated using standard techniques well known to one of ordinary skill in the art, such as recrystallization techniques, flash chromatography or chiral chromatography.
It is readily appreciated by one of ordinary skill in the art that piperidines of structure (16) [see Schemes III and IV below], wherein B represents: 
can be prepared under standard conditions, such as in a manner analogous to the procedures set forth in Schemes I through IIA for preparation of the piperidines described therein.
Compounds of formula I are prepared following generally the procedure set forth in Scheme III. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. 
In Scheme III, step A, compound (13) is coupled with compound (14) under standard conditions well known in the art, to provide compound (15). For example, compound (13) is dissolved in a suitable organic solvent, such as DMF, and treated with about one equivalent of a suitable base, such as sodium hydride. To the stirring solution is added about 1.1 equivalents of compound (14) and the reaction is stirred at about xe2x88x9210xc2x0 C. to room temperature for about 20 minutes to 1 hour. Compound (15) is then isolated and purified by techniques well known in the art, such as extraction techniques and flash chromatography. For example, the reaction mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude material. The crude material can be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
In Scheme III, step B compound (15) is coupled with piperidine (16) under standard conditions well known in the art to provide the compound of formula I. For example, compound (15) is dissolved in a suitable organic solvent, such as dimethylformamide with about one equivalent of a suitable neutralizing agent, such as sodium bicarbonate. To this mixture is added about one equivalent of a piperidine (16) and the mixture is heated at about 70xc2x0 C. to 90xc2x0 C. for about 4 hours to 12 hours. The compound of formula I is then isolated and purified by techniques well known in the art, such as extraction techniques and flash chromatography. For example, the reaction mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude material. The crude material can be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
Compounds of formula Ia are prepared following generally the procedure set forth in Scheme IV. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. 
In Scheme IV, step A, the compound of structure (13) is coupled with the epoxide (17) to provide the epoxide (18). For example, compound (13) is dissolved in a suitable organic solvent, such as dimethylformamide and cooled to 0xc2x0 C. About 1.1 equivalents of sodium hydride is added to the solution which is then stirred for about one hour. A solution of one equivalent of the epoxide (17) in dimethylformamide is then added dropwise to the solution. The reaction mixture is then stirred for about 1 to 24 hours at 0xc2x0 C. It is then quenched with water. The resulting solution is extracted with a suitable organic solvent, such as ethyl acetate. The organic layers are combined, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to provide crude epoxide (18). The crude product can be purified by crystallization with a suitable solvent, such as dichloromethane or by flash chromatography on silica gel with a suitable eluent, such as dichloromethane/hexane.
In Scheme IV, step B, the epoxide (18) is opened with the substituted piperidine of structure (16) under standard conditions well known in the art, such as those disclosed by Krushinski, et al. in U.S. Pat. No. 5,576,321, issued Nov. 19, 1996, to provide the compound of formula Ia. For example, epoxide (18), such as (S)-(+)-4-(oxiranylmethoxy)-1H-indole is dissolved in a suitable organic solvent, such as methanol, and treated with about one equivalent of piperidine (16). The solution is then heated to reflux for about 8 to 12 hours and then cooled to room temperature. The reaction mixture is then concentrated under vacuum and the crude residue is purified and resulting stereoisomers separated from each other by techniques well known in the art, such as flash chromatography, radial chromatography or high performance liquid chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
The following examples are illustrative only and represent typical syntheses of the compounds of formula I and formula Ia as described generally above. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: xe2x80x9ceqxe2x80x9d or xe2x80x9cequiv.xe2x80x9d refers to equivalents; xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9cmgxe2x80x9d refers to milligrams; xe2x80x9cLxe2x80x9d refers to liters; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cxcexcLxe2x80x9d refers to microliters; xe2x80x9cmolxe2x80x9d refers to moles; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9cpsixe2x80x9d refers to pounds per square inch; xe2x80x9cminxe2x80x9d refers to minutes; xe2x80x9chxe2x80x9d refers to hours; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography; xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography; xe2x80x9cRfxe2x80x9d refers to retention factor; xe2x80x9cRtxe2x80x9d refers to retention time; xe2x80x9cxcex4xe2x80x9drefers to parts per million down-field from tetramethylsilane; xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran; xe2x80x9cDMFxe2x80x9d refers to N,N-dimethylformamide; xe2x80x9cDMSOxe2x80x9d refers to methyl sulfoxide; xe2x80x9cLDAxe2x80x9d refers to lithium diisopropylamide; xe2x80x9caqxe2x80x9d refers to aqueous; xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate; xe2x80x9ciPrOAcxe2x80x9d refers to isopropyl acetate; xe2x80x9cMeOHxe2x80x9d refers to methanol; xe2x80x9cMTBExe2x80x9d refers to tert-butyl methyl ether, and xe2x80x9cRTxe2x80x9d refers to room temperature.
Preparation of 1-Bromo-5-methoxy-naphthalene. 
Preparation of 5-Bromo-3,4-dihydro-1(2H)-naphthalenone and 7-Bromo-3,4-dihydro-1(2H)-naphthalenone.
Anhydrous AlCl3 (66.67 g, 0.50 mol, 99.99%) under N2 was stirred vigorously as 1-tetralone (29.83 g, 0.20 mol) was added dropwise over xcx9c7 min. The evolved HCl gas was scrubbed through 5 N NaOH. The resulting mixture was a dark brown oil that exothermed to 75xc2x0 C. When the temperature had cooled to 50xc2x0 C., Br2 was added dropwise over 15 min. The mixture, which had cooled further to 40xc2x0 C., was heated to 80xc2x0 C. for 5 min, then poured into a mixture of ice (600 g) and 12 N HCl (80 mL). All the ice melted, leaving a cool dark mixture which was diluted with H2O (200 mL) and extracted with CH2Cl2 (200 mL, 100 mL). The combined extracts were dried with MgSO4 and concentrated in vacuo (30-60xc2x0 C.) to a dark brown oil (45.6 g; theory=45.02 g).
Chromatography over silica gel 60 with 8:1 heptane:THF did not prove effective, but two passes through the Biotage radially pressured silica gel cartridges using 9:1 heptane:MTBE as eluent produced acceptably pure fractions.
5-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as an orange oil (12.27 g, 28.3%). HPLC showed an apparent wide divergence in absorbances at 230 nm for the two regioisomers, and was therefore not reliable for a potency check. TLC on silica gel (4:1 heptane:MTBE) confirmed modest contamination with 7-bromo-3,4-dihydro-1(2H)-naphthalenone.
7-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as a yellowish-white solid (15.48 g, 35.8%); mp 69.5-75xc2x0 C. (lit 74-75xc2x0 C.). 1H NMR (CDCl3) corresponded to the literature description, plus a trace of heptane and an undefined by-product. TLC showed it to be cleaner than 5-bromo-3,4-dihydro-1(2H)-naphthalenone.
A third fraction of orange oil (9.06 g, 20.9%) was isolated. TLC showed it to be a nearly 1:1 ratio of 5-bromo-3,4-dihydro-1(2H)-Naphthalenone, and 7-bromo-3,4-dihydro-1(2H)-Naphthalenone.
Preparation of 2,5-Dibromo-3,4-dihydro-1(2H)-naphthalenone.
A clear yellow solution of 5-bromo-3,4-dihydro-1(2H)-Naphthalenone(12.09 g, 53.7 mmol) in freshly opened Et2O (220 mL) under an N2 atmosphere was chilled to xe2x88x925xc2x0 C. HCl was bubbled in subsurface for 1 min, causing no visible change. The dropwise addition of a solution of Br2 (8.58 g, 53.7 mmol) in CH2Cl2 (20 mL) and Et2O (2 mL) to the vigorously stirring solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each drop was allowed to fully decolorize before adding the next) produced a product mixture that assayed by HPLC. Peak area showed 79.4% title compound, 9.5% unreacted 5-bromo-3,4-dihydro-1(2H)-naphthalenone, 0.6% unidentified, and 9.4% 2,2,5-tribromo-1-tetralone. The addition of H2O produced a top light brown organic phase, and a clear, colorless bottom aqueous phase which was separated. After drying with MgSO4, the organic layer was concentrated in vacuo at room temperature to give the crude intermediate title compound as a light brown oil (16.08 g, 98.5%).
Preparation of 5-Bromo-1-naphthalenol.
The crude mixture of 2,5-dibromo-1-tetralone (16.08 g, 52.9 mmol,), LiCl (5.61 g, 132 mmol), and 120 mL of dry DMF were combined under an N2 atmosphere and heated to reflux (xcx9c155xc2x0 C.). The mixture turned dark brown. HPLC showed complete consumption of the starting material in just 0.5 h. After cooling to room temperature, the mixture was diluted with 1 N HCl (200 mL) and extracted three times with Et2O (100 mL, 25 mL, 25 mL). The Et2O layers were combined to give a brown hazy mixture (some emulsion). After stirring with decolorizing carbon (10 g, Calgon ADP) and filtration through hyflo supercel, a clear light yellow solution was obtained. This solution was extracted with 3 N NaOH (100 mL, 25 mL), leaving the non-naphtholic byproducts behind. The brown NaOH extracts were combined, acidified to pH 1 with conc. HCl, and extracted with CH2Cl2 (100 mL, 25 mL). The combined CH2Cl2 layers formed a deep red solution. After stirring with decolorizing carbon (5 g, Darco G-60) and filtration through hyflo supercel, the solution was again light yellow. An equal volume of heptane was added, and the CH2Cl2 was distilled away. When the temperature reached 75xc2x0 C., gray precipitate became evident. This increased substantially on cooling to room temperature. Following filtration and drying in vacuo at 50xc2x0 C., a product mixture of gray solid (5.92 g, 50.2%) was obtained. HPLC showed this to be a mixture of 7-bromo-1-naphthol (48.3%) and 5-bromo-1-naphthol (50.8%). However, 1H NMR (CDCl3) integration showed that the actual ratio was about 9/1 5-Br/7-Br. Preparative reverse phase HPLC gave one peak of 5-bromo-1-naphthol as a white solid (3.22 g, 27.3%).
Preparation of the Final Title Compound.
Purified 5-bromo-1-naphthol (3.22 g, 14.4 mmol), was dissolved in CH3CN (50 mL), giving a clear and nearly colorless solution. Dimethylsulfate (2.72 g, 21.6 mmol, 1.5 equiv), K2CO3 (3.0 g, 21.6 mmol), and tetrabutylammonium bromide (TBAB, 20 mg) as phase transfer catalyst were added, and the resulting mixture was stirred for 16 h. HPLC revealed no detectable starting material, so H2O (50 mL) was added. The inorganic salt promptly dissolved, followed immediately by crystallization of the product. Following filtration, an H2O wash (50 mL) of the cake, and drying in vacuo at 50xc2x0 C., provided the final title compound as a light tan crystalline solid (3.07 g, 90.0%) in outstanding purity: mp 68.5-69.5xc2x0 C. Clean 1H and 13C NMR (CDCl3) spectra. Satisfactory elemental analysis was obtained when block dried at 60xc2x0 C. Purity of 99.6% by HPLC.
Preparation of 2-Bromo-7-methoxy-naphthalene. 
Preparation of 7-Bromo-2-naphthalenol.
Triphenyl phosphine (89.7 g, 0.342 mol) and acetonitrile (350 mL) were combined in a 1-L flask under N2 atmosphere. The mixture was cooled to 10xc2x0 C. Bromine (17.6 mL, 0.342 mol) was added dropwise over 10 minutes. The cooling bath was removed and 2,7-dihydroxynaphthalene (50.0 g, 0.312 mol) was added along with 350 mL of CH3CN rinse. The resulting yellow tan mixture was heated at reflux for 3 hours. Acetonitrile was distilled off using a water aspirator over 2 hours resulting in a grayish white solid. The solid was heated to 280xc2x0 C. over 30 minutes giving a black liquid. The liquid was heated to 310xc2x0 C. over 20 minutes and the temperature was maintained at 310xc2x0 C. for an additional 15 minutes until gas evolution ceased. The black mixture was cooled to room temperature. Chromatography yielded 34.5 g of the intermediate title compound as an off-white solid which was 87% pure by HPLC (43% yield).
Preparation of the Final Title Compound.
2-Bromo-7-hydroxynaphthalene (34.1 g, 0.134 mol), DMF (290 mL) and powdered potassium carbonate (31.8 g, 0.230 mol) were combined in a 500-mL flask under N2 atmosphere. Methyl iodide (14.3 mL, 0.230 mol) was added at once and the dark yellow mixture was stirred vigorously at room temperature for 3xc2xe hours. Water (290 mL) was added dropwise over 15 minutes to induce crystallization. The mixture was stirred at room temperature for 1 hour. The product was filtered off and washed with 200 mL of a 1:1 mixture of DMF and water. The solid was dried in vacuo at 50xc2x0 C. to yield 32.6 g of pale yellow solid (HPLC: 89%). The solid was dissolved in 300 mL of boiling MeOH. The hot solution was filtered, then placed in the freezer overnight. The resulting crystals were filtered and washed with 100 mL of cold MeOH. The solid was dried in vacuo at 50xc2x0 C. to give 27.0 g of pale yellow solid (HPLC: 95%). The solid was dissolved in 100 mL of boiling i-PrOH then allowed to cool to room temperature. The resulting solid was filtered and washed with 100 mL of i-PrOH. The solid was dried in vacuo at 50xc2x0 C. to yield 22.8 g of the title compound as pale yellow crystals.
Preparation of 6-Iodo-1-methoxy-naphthalene. 
Preparation of 5-Bromo-2-naphthalenecarboxylic Acid.
2-Naphthoic acid (50.0 g, 0.290 mol), glacial acetic acid (250 mL), bromine (15 mL, 0.291 mol) and iodine (1.3 g, 0.005 mol) were combined in a flask under N2 atmosphere. The mixture was heated at reflux for 35 minutes then cooled to room temperature. The thick yellow mixture was stirred at room temperature for 1 hour. The mixture was filtered and the pale orange solid was rinsed with xcx9c100 mL of the filtrate. The solid was dried in vacuo at 55xc2x0 C. overnight to yield 55.5 g of pale orange solid. The solid was slurried in 275 mL of 1 N NaOH for 30 minutes. The solid was filtered off and rinsed 3 times with 50 mL portions of the filtrate. The solid was air dried in the hood over the weekend to yield 46.7 g of solid. The solid was added to 220 mL of water. Concentrated HCl (15 mL) was added to obtain pH of 1.3 and the mixture was stirred for 4 hours. The solid was filtered off and washed with 200 mL of water. The solid was dried in vacuo at 50xc2x0 C. to give 37.6 g of intermediate title compound as white crystals (HPLC: 90% with 9% 2-naphthoic acid, 46% yield).
Preparation of 5-Bromo-2-naphthalenecarboxylic Acid, Methyl Ester.
5-Bromo-2-naphthoic acid (17.33 g, 69 mmol) and 250 mL of MeOH were combined in a flask under N2 atmosphere. Thionyl chloride (5.84 mL, 80 mmol) was added dropwise over 15 minutes at a temperature of 25-30xc2x0 C. resulting in a pale yellow mixture. The mixture was heated at reflux for 3xc2xc hours. The resulting yellow solution was concentrated in vacuo to 137.4 g of solution then placed in the freezer overnight. The resulting thick mixture was filtered and the solid was washed with 100 mL of cold MeOH. The solid was dried in vacuo at 50xc2x0 C. to give 11.39 g of intermediate title compound as white crystals. A second crop was filtered and washed with 100 mL of cold MeOH. The solid was dried to 1.31 g of white crystals. Yield: 69%, 2 crops.
Preparation of 5-Methoxy-2-naphthoic Acid.
A 25% solution of sodium methoxide in MeOH (63 mL, 0.258 mol) was added to a 500-mL flask under N2 atmosphere. Cupric iodide (recrystallized, 4.19 g, 22 mmol), 160 mL of pyridine, 160 mL of MeOH and methyl 5-bromo-2-naphthoate (11.39 g, 43 mmol) were added to the flask to give a yellow green mixture. The mixture was heated at reflux for 30 hours. The mixture was cooled to room temperature and water (850 mL) was added resulting in a rust colored mixture having pH of 12.8. The pH was adjusted to 1.0 by addition of concentrated HCl resulting in a white precipitate. The mixture was cooled to 10xc2x0 C., filtered and the solid was washed with cold water. The solid was dried to 11.03 g white crystals. The solid was taken up in 200 mL of EtOAc and 150 mL of water. The pH of the mixture was 3.5. The pH was adjusted to 10.0 by addition of 5 N NaOH and maintained for 4 hours. The EtOAc was removed by concentration in vacuo then the pH was adjusted to 1.0 by addition of concentrated HCl. The mixture was placed in a freezer overnight. The mixture was filtered and the solid was washed with water until the filtrate stream was colorless. The solid was dried in vacuo at 50xc2x0 C. to give 9.77 g of off-white solid. The solid was added to 50 mL of 2.5 N NaOH and the thick orange mixture was stirred for 3 hours. The pH was adjusted to 1.0 with concentrated HCl. The mixture was filtered and the solid was washed with water. The solid was dried to 9.43 g of off-white solid. The solid was dissolved in 200 mL of boiling MeOH and the hot solution was filtered then cooled to room temperature. Water (300 mL) was added and the mixture was stirred at room temperature for 2 hours. The solid was filtered off and washed with 100 mL of a 1:1 mixture of MeOH and water. The solid was dried in vacuo at 50xc2x0 C. to give 7.18 g of intermediate title compound as a white solid (HPLC: 97%, 83% yield).
Preparation of 5-Methoxy-2-Naphthylamine.
5-Methoxy-2-naphthoic acid (3.17 g, 15.7 mmol), CH2CO2 (38 mL) and DMF (3.04 mL, 39.2 mmol) were combined in a 50-mL flask under a N2 atmosphere. Oxalyl chloride (2.73 mL, 31.3 mmol) was added dropwise over 30 minutes at 20 to 23xc2x0 C. The resulting yellow solution was stirred at room temperature for 15 minutes. The solution was then concentrated in vacuo to 6.48 g of yellow solid which was slightly wet with DMF. The solid was dissolved in CH3CN (157 mL) and added dropwise over 35 minutes to a solution of sodium azide (2.55 g, 39.2 mmol) in 24 mL of water, and rinsed in with an additional 25 mL of CH3CN. Analysis of the resulting yellow mixture by HPLC after 5 minutes showed 15% acyl chloride remaining. Water (15 mL) was added to give an orange mixture and to promote acyl azide formation. The mixture was heated at reflux for 1 hour and 40 minutes. The mixture was cooled to room temperature. Sodium hydroxide (50 mL, 2N solution) was added and the resulting yellow mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to 102.0 g of brown gum plus liquid. The mixture was extracted with 50 mL of CH2Cl2. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated in vacuo to provide 1.83 g of the intermediate title compound as a brown oil (HPLC: 91%, 61% yield).
Preparation of the Final Title Compound.
2-Amino-5-methoxynaphthalene (1.78 g, 9.35 mmol), 5 mL of concentrated HCl(aq), 5 mL of water and 10 g of ice were combined in a flask. The tan orange mixture was cooled to 5xc2x0 C. A chilled solution of sodium nitrite (0.75 g, 10.8 mmol) in 4 mL of water was added over 5 minutes keeping the temperature below 10xc2x0 C. The mixture was stirred at 5xc2x0 C. for 30 minutes. A solution of potassium iodide (1.71 g, 10.3 mmol) in 10.5 mL of water was added, the bath was removed and the orange solution plus black solid was stirred at room temperature. Analysis by HPLC showed that more KI was needed. Potassium iodide (7.2 g, 43.4 mmol), 100 mL of CH3CN and 50 mL of acetone were added and the mixture was stirred for 22 hours at room temperature. The mixture was extracted with 150 mL of Et2O. The Et2O phase was washed successively with 200 mL of 5% NaHSO3(aq), 200 mL of 5% NaHCO3(aq), 200 mL of water and 200 mL of saturated NaCl solution. The Et2O phase was dried over Na2SO4, filtered and concentrated in vacuo to yield 2.21 g of dark brown solid (HPLC: 69.5%). The solid was adsorbed onto 8.0 g of silica gel 60 in CH2Cl2 then concentrated to a powder. The powder was slurried in hexane and chromatographed on 100 g of silica gel 60 at atmospheric pressure, eluting with hexane. The desired final title compound was collected (1.33 g, 50% yield) as a white solid after concentration of the appropriate fractions.
Preparation of N-(t-Butyloxycarbonyl)-2-methyl-4-piperidone. 
A solution of the following protected amine; 
(145 g, prepared in a manner analogous to the procedures described by Hall, H. K. Jr., J. Am. Chem. Soc., 79, 5444 (1957) and Harper, N. J.; Beckett, A. H.; Balon, A. D. J., J. Chem. Soc., 2704 (1960)) dissolved in THF (200 mL) was added dropwise over one hour to a cooled solution of potassium t-butoxide (58.9 g) in THF (500 mL). The mixture was stirred at 0xc2x0 C. for 2.5 hours and then warmed to room temperature over 1 hours with stirring. Another 50 mL of 1.0 M potassium t-butoxide in THF was added. After one hour, the solvent was removed under vacuum and the residue was dissolved in ethyl acetate (1 L). The organic solution was washed with saturated ammonium chloride (2xc3x97500 mL) which was back extracted with ethyl acetate (2xc3x97500 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 120. 6 g of crude material as an oil. This oil was then treated with 5 N HCl (700 mL) at reflux for about 14.5 hours. After cooling, the solution was rinsed with a mixture of ethyl acetate/diethyl ether (1:1, 2xc3x97300 mL). The aqueous layer was then concentrated to provide the piperidone salt of structure: 
The above piperidone salt was then dissolved in water (200 mL) and THF (250 mL). The solution was then cooled to 0xc2x0 C. and treated with 50% sodium hydroxide (35 mL) followed by dropwise addition of tert-butoxycarbonyl anhydride (106.7 g) in THF (100 mL) over one hour. The ice bath was then removed and the solution was stirred at room temperature for about 4 days. The pH was then adjusted to about 8 to 9. The THF was then removed under vacuum and the mixture is taken up in ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2xc3x97500 mL). The organic extracts were combined, washed with brine (300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to provide 36.81 g of title compound.
Preparation of N-(t-Butyloxycarbonyl)-2,2-dimethyl-4-piperidone 
In a manner analogous to the procedure described in preparation 4 above, the title compound can be prepared from the following starting material; 
Preparation of N-Benzyl-3,3-dimethyl-4-piperidone. 
In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10xc2x0 C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4%. MS(ion spray)=218.3 (M+1)